1. Technical Field
The present invention relates to substantially purified tumor growth inhibiting factor (TIF). More particularly, the present invention is directed to substantially purified polypeptide factors capable of inhibiting the growth of certain cancer cells without adversely affecting the growth of certain normal human cells.
2. Discussion of the Prior Art
A wide variety of tumor growth factors (TGF) and growth inhibitory substances are known in the art. Holley et al., Proc. Natl. Acad. Sci. USA 77:5989, 1980 and Holley et al. Cell Biol. Int. Reports 7, 525-526 (1983), have reported the isolation of a potent growth inhibitor from African green monkey kidney BSC-1 cells, which was found to inhibit the growth of the producer cell as well as human mammary tumor cells and normal human mammary cells. McMahon et al. (1982) Proc. Natl. Acad. Sci. USA 79, 456-460 have purified a 26,000 M.sub.r (relative molecular weight) inhibitor of cell proliferation from rat liver which affects nonmalignant rat liver cells, but does not affect the proliferation of malignant rat liver cells. Other growth inhibitors have been found in cultured chick spinal cord cells (Kagen, et al (1978) Experimental Neurology 58, 347-360; Harrington, et al (1980) Proc. Natl. Acad. Sci. USA 77, 423-427; and Steck, et al (1979) J. Cell Biol. 83, 562-575).
Bichel (1971) Nature 231, 449-450 reported that aspiration of most of the tumor from mice bearing ascites tumors at a plateau of growth was followed by a marked increase in growth of the remaining tumor cells. Injection of cell-free ascites, obtained from mice bearing fully developed ascites tumors, into mice with growing ascites tumors resulted in a pronounced inhibition of ascites growth. Bichel, supra, also observed that two surgically joined mice (parabiotic), one mouse with an advanced tumor and the other with an early tumor, resulted in a pronounced inhibition of growth of the early tumor. These observations Bichel (1970) Europ. J. Cancer 6, 291-296 and Bichel, supra, were explained by the existence of a diffusible inhibitory principle which circulated through the peritoneum of the parabiotic mice and was present in the cell-free ascites fluid produced by the fully developed ascites tumors. The nature of this inhibiting principle was not characterized, but the speculation was that the rate of growth of the ascites tumors depended upon the amount of tumor tissue present in the mouse and the amount of tumor tissue determining the amount of the inhibitory principle produced.
Todaro et al, Bristol-Myers Cancer Symposium 4:222-223, 1982, reported some properties of certain tumor cell growth inhibitory factors. Not only the observations made by Todaro et al, supra, were preliminary, based on partially purified preparations, but the TIFs of the present invention differ from those of the prior art in several fundamental respects:
(1) Whereas the TIFs of the prior art block TGF-dependent growth of normal cells, the TIFs of the present invention are noninhibitory to the TGF-dependent growth of normal cells.
(2) Whereas the prior art wondered whether there were different families or types of inhibitory factors, the present invention has in fact isolated, substantially purified and established at least two different kinds of TIFs not only distinct from the prior art but distinguishable from each other; and
(3) Unlike the TIFs previously known, the TIFs of the present invention possess a novel mitogenic and human cell growth stimulating property.